The mechanisms by which individuals acquire immunity to malaria are poorly understood and although antibodies are thought to be central, evidence that specific anti-malarial antibodies are associated with protection from clinical episodes of malaria has been conflicting. I hypothesized that the breadth (number of important targets to which antibodies were made) and magnitude (antibody level measured in a random serum sample) of the antibody response were important predictors of protection from clinical malaria. I also investigated whether allele-specific antibodies protected children from developing clinical'episodes of malaria associated with parasites bearing homologous alleles. I analyzed naturally-acquired antibodies to five leading P.falciparum merozoite stagevaccine candidate antigens, and schizont extract, in Kenyan children monitored longitudinally for mild and severe malaria. I also genotyped parasites from clinical episodes to investigate allele-specific antibody-mediated immunity. Serum antibody levels to apical membrane antigen 1 (AMA1), and merozoite surface protein antigens (MSP-l block 2, MSP-2, MSP-3) were inversely related to the probability of developing malaria, but levels to MSP-119 and erythrocyte binding antigen (EBA-17S) were not. The risk of mild malaria was also inversely associated with increasing breadth of antibody specificities, with none of the children who simultaneously had high antibody levels to five or more antigens experiencing a clinical episode, (17/119,15%) P=O.0006. Particular combinations of antibodies (AMA1, MSP-2, MSP-3) were more strongly predictive of protection than others. The results were validated in a larger, separate case control study whose end-point was malaria severe enough to warrant hospital admission (n=387). I found little evidence that allele-specific antibodies conferred protection against clinical episodes associated with parasites bearing homologous alleles. These findings suggest that under natural exposure, immunity to malaria may result from high titre antibodies to multiple antigenic targets and support the idea of testing combination blood stage vaccines optimized to induce similar antibody profiles.